β-Amino acids are of interest in the preparation of active pharmaceutical ingredients (APIs). The β-amino acid moiety in APIs of interest is normally part of a complex whole structure. Complexity is typically enhanced when considering a chiral center at the β-position of the β-aminobutyryl group and the general desire to obtain enantiopure compounds.
A particularly interesting class of APIs having β-amino acid structural moieties are dipeptidyl peptidase-4 (DPP-4) inhibitors which act as antidiabetic agents. DPP-4 inhibitors are oral antidiabetic drugs, which reduces glucose blood levels by a new mechanism of action in which the DPP-4 inhibitors (“gliptins”) inhibit inactivation of glucagon-like peptide (GLP), which stimulates insulin secretion. The benefit of these medicines lies in its lower side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values. It can be used for treatment of diabetes mellitus type 2 either alone or in combination with other oral antihyperglycemic agents, such as metformin or a thiazolidinediones.
The first member of the novel pharmacological group is sitagliptin (compound of formula I), which is chemically (R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one and which structure includes a β-amino acid part.

However, an inclusion of an 3-amino acid framework into more complex molecules remains a permanent challenge for industrial production.
This is well reflected in the literature for the synthesis of sitagliptin. Several methods are described, how to introduce the β-amino acid structure into the molecule of sitagliptin. The first synthesis of sitagliptin molecule used chiral unusual dihydropyrazine chiral promoters, diazomethane and silver salts (WO 03/004498) which are unacceptable reagents for industrial synthesis—Scheme 1.

Better approaches include enantioselective hydrogenation of β-enamino acid derivatives but they need expensive precious metal catalysts, such as rhodium (WO 03/004498, Tetrahedron Asymmetry 17, 205 (2006)) or ruthenium (WO 09/064,476) and expensive ligands, such as ferrocenyl diphosphine ligands—JOSIPHOS catalysts (WO 04/085378, WO 05/097733, WO 06/081151, J. Am. Chem. Soc., 126, 9918 (2004)).

Another option is a hydrogenation with cheaper achiral catalyst, but with chiral derivatisation of enamines derived from phenylglycinamide—Scheme 3 (WO 04/085661). The obtained e.e. values are not sufficient for pharmaceutical use.

Yet another option is creating chiral centers by selective reduction of β-keto acid derivatives. Precious metal catalysts (WO 04/087650, Org. Prep. Res. & Dev. 9, 634-639 (2005)) or enzymatic reduction (WO 09/045,507) can be used, while the transformation of the obtained chiral hydroxyl intermediates to final sitagliptin precursors via azetidinone intermediates is laborious—Scheme 4.

Most of described routes use 2,4,5-trifluorophenylacetic acid derivatives as starting materials which are prepared from 1-bromo-2,4,5-trifluorobenzene via organometal intermediates using copper (US 2004/068141), magnesium (US 2004/077901) and cobalt (CN 1749232) containing reagents. Organometals have been routinely used in industrial synthesis, but it is still more wished to avoid them, because their use requires more expensive special equipment.
Therefore, there is still a need for a simplification of industrial synthesis of β-amino acid derivatives as intermediates in the synthesis of dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin.